The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms
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PROVIDER: S-EPMC10549934 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Abdominal aortic aneurysm (AAA) can be fatal if ruptured, but there is no predictive biomarker. Our aim was to evaluate the prognostic potential of microRNAs (miRNAs/miRs) in an AAA mouse model and patients with unruptured AAA (URAAA) and ruptured AAA (RAAA). Among the 64 miRNAs differentially expressed in mice with AAA compared to control, miR-30c-1-3p, miR-432-3p, miR-3154, and miR-379-5p had high homology with human miRNAs. MiR-30c-1-3p plasma levels were significantly lower in patients with RAAA than in those with URAAA or control and tended to negatively correlate with the maximum aortic diameter (r = -0.3153, P = 0.06109). MiR-30c-1-3p targeted matrix metalloproteinase (MMP)-9 mRNA through the coding region and downregulated its expression in vitro. MMP-9 plasma concentrations were significantly higher in the RAAA group than in the URAAA group (P < 0.001) and were negatively associated with miR-30c-1-3p levels (r = -0.3671, P = 0.01981) and positively-with the maximal aortic diameter (r = 0.6251, P < 0.0001). The optimal cutoff values for MMP-9 expression and the maximal aortic diameter were 461.08 ng/ml and 55.95 mm, with areas under the curve of 0.816 and 0.844, respectively. Our results indicate that plasma levels of miR-30c-1-3p and MMP-9 may be candidate biomarkers of AAA progression. KEY MESSAGES: Downregulation of miR-30c-1-3p expression and upregulation of its potential target MMP-9 are predictors of the devastation of AAA. Downregulation of miR-30c-1-3p expression and its downstream impact on MMP-9 have a potential on predicting the development and rupture of AAA.
| S-EPMC9329399 | biostudies-literature
Project description:BackgroundAbdominal aortic aneurysm (AAA) is a life-threatening disease that lacks effective preventive therapies. This study aimed to evaluate the effect of pemafibrate, a selective peroxisome proliferator-activated receptor alpha (PPARα) agonist, on AAA formation and rupture.MethodsExperimental AAA was induced by subcutaneous angiotensin II (AngII) infusion in ApoE - / - mice for 4 weeks. Pemafibrate (0.1 mg/kg/day) was administered orally. Dihydroethidium staining was used to evaluate the reactive oxygen species (ROS).ResultsThe size of the AngII-induced AAA did not differ between pemafibrate- and vehicle-treated groups. However, a decreased mortality rate due to AAA rupture was observed in pemafibrate-treated mice. Pemafibrate ameliorated AngII-induced ROS and reduced the mRNA expression of interleukin-6 and tumor necrosis factor-α in the aortic wall. Gelatin zymography analysis demonstrated significant inhibition of matrix metalloproteinase-2 activity by pemafibrate. AngII-induced ROS production in human vascular smooth muscle cells was inhibited by pre-treatment with pemafibrate and was accompanied by an increase in catalase activity. Small interfering RNA-mediated knockdown of catalase or PPARα significantly attenuated the anti-oxidative effect of pemafibrate.ConclusionPemafibrate prevented AAA rupture in a murine model, concomitant with reduced ROS, inflammation, and extracellular matrix degradation in the aortic wall. The protective effect against AAA rupture was partly mediated by the anti-oxidative effect of catalase induced by pemafibrate in the smooth muscle cells.
| S-EPMC9280056 | biostudies-literature
Project description:Vitamin D deficiency has been associated with human abdominal aortic aneurysm (AAA); however, its role in AAA pathogenesis is unclear. The aim of the present study was to investigate the effect of vitamin D deficiency on AAA development and examine if administering cholecalciferol (CCF) could limit growth of established AAA within the angiotensin-II (AngII) infused apolipoprotein E-deficient mouse model. Mice were rendered vitamin D deficiency through dietary restriction and during AngII infusion developed larger AAAs as assessed by ultrasound and ex vivo morphometry that ruptured more commonly (48% vs. 19%; P=0.028) than controls. Vitamin D deficiency was associated with increased aortic expression of osteopontin and matrix metalloproteinase-2 and -9 than controls. CCF administration to mice with established aortic aneurysms limited AAA growth as assessed by ultrasound (P<0.001) and ex vivo morphometry (P=0.036) and reduced rupture rate (8% vs. 46%; P=0.031). This effect was associated with up-regulation of circulating and aortic sclerostin. Incubation of human aortic smooth muscle cells with 1,25-dihyroxyvitamin D3 (the active metabolite of vitamin D) for 48 h induced up-regulation of sclerostin (P<0.001) and changed the expression of a range of other genes important in extracellular matrix remodeling. The present study suggests that vitamin D deficiency promotes development of large rupture-prone aortic aneurysms in an experimental model. CCF administration limited both growth and rupture of established aneurysms. These effects of vitamin D appeared to be mediated via changes in genes involved in extracellular matrix remodeling, particularly sclerostin.
| S-EPMC7536319 | biostudies-literature
Project description:Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP-13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms.
| S-EPMC2751539 | biostudies-literature
Project description:Abdominal aortic aneurysms (AAAs), which commonly occur among elderly individuals, are accompanied by a risk of rupture and subsequent high mortality. Establishment of medical therapies for the prevention of AAAs requires further understanding of the molecular pathogenesis of this condition. This report details the possible involvement of Osteoprotegerin (OPG) in the prevention of AAAs through inhibition of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In CaCl2-induced AAA models, both internal and external diameters were significantly increased with destruction of elastic fibers in the media in Opg knockout (KO) mice, as compared to wild-type mice. Moreover, up-regulation of TRAIL expression was observed in the media by immunohistochemical analyses. Using a culture system, both the TRAIL-induced expression of matrix metalloproteinase-9 in smooth muscle cells (SMCs) and the chemoattractive effect of TRAIL on SMCs were inhibited by OPG. These data suggest that Opg may play a preventive role in the development of AAA through its antagonistic effect on Trail.
| S-EPMC4718675 | biostudies-literature
Project description:The cardiovascular field is still searching for a treatment for abdominal aortic aneurysms (AAA). This inflammatory disease often goes undiagnosed until a late stage and associated rupture has a high mortality rate. No pharmacological treatment options are available. Three hallmark factors of AAA pathology include inflammation, extracellular matrix remodeling, and vascular smooth muscle dysfunction. Here we discuss drugs for AAA treatment that have been studied in clinical trials by examining the drug targets and data present for each drug's ability to regulate the aforementioned three hallmark pathways in AAA progression. Historically, drugs that were examined in interventional clinical trials for treatment of AAA were repurposed therapeutics. Novel treatments (biologics, small-molecule compounds etc.) have not been able to reach the clinic, stalling out in pre-clinical studies. Here we discuss the backgrounds of previous investigational drugs in hopes of better informing future development of potential therapeutics. Overall, the highlighted themes discussed here stress the importance of both centralized anti-inflammatory drug targets and rigor of translatability. Exceedingly few murine studies have examined an intervention-based drug treatment in halting further growth of an established AAA despite interventional treatment being the therapeutic approach taken to treat AAA in a clinical setting. Additionally, data suggest that a potentially successful drug target may be a central inflammatory biomarker. Specifically, one that can effectively modulate all three hallmark factors of AAA formation, not just inflammation. It is suggested that inhibiting PGE2 formation with an mPGES-1 inhibitor is a leading drug target for AAA treatment to this end.
| S-EPMC9514980 | biostudies-literature
Project description:A rupture risk assessment is critical to the clinical treatment of abdominal aortic aneurysm (AAA) patients. The biomechanical AAA rupture risk assessment quantitatively integrates many known AAA rupture risk factors but the variability of risk predictions due to model input uncertainties remains a challenging limitation. This study derives a probabilistic rupture risk index (PRRI). Specifically, the uncertainties in AAA wall thickness and wall strength were considered, and wall stress was predicted with a state-of-the-art deterministic biomechanical model. The discriminative power of PRRI was tested in a diameter-matched cohort of ruptured (n = 7) and intact (n = 7) AAAs and compared to alternative risk assessment methods. Computed PRRI at 1.5 mean arterial pressure was significantly (p = 0.041) higher in ruptured AAAs (20.21(s.d. 14.15%)) than in intact AAAs (3.71(s.d. 5.77)%). PRRI showed a high sensitivity and specificity (discriminative power of 0.837) to discriminate between ruptured and intact AAA cases. The underlying statistical representation of stochastic data of wall thickness, wall strength and peak wall stress had only negligible effects on PRRI computations. Uncertainties in AAA wall stress predictions, the wide range of reported wall strength and the stochastic nature of failure motivate a probabilistic rupture risk assessment. Advanced AAA biomechanical modelling paired with a probabilistic rupture index definition as known from engineering risk assessment seems to be superior to a purely deterministic approach.
| S-EPMC4707859 | biostudies-literature
Project description:Objective/backgroundBiomarker(s) for prediction of the future progression rate of abdominal aortic aneurysms (AAA) may be useful to stratify the management of individual patients. AAAs are associated with features of systemic inflammation and endothelial dysfunction. Flow mediated dilatation (FMD) of the brachial artery is a recognised non-invasive measurement for endothelial function. We hypothesised that FMD is a potential biomarker of AAA progression and reflects the temporal changes of endothelial function during AAA progression.MethodsIn a prospectively recruited cohort of patients with AAAs (Oxford Abdominal Aortic Aneurysm Study), AAA size was recorded by antero-posterior diameter (APD) (outer to outer) on ultrasound. Annual AAA progression was calculated by (ΔAPD/APD at baseline)/(number of days lapsed/365 days). FMD was assessed at the same time as AAA size measurement. Analyses of data were performed in the overall cohort, and further in subgroups of AAA by size (small: 30-39 mm; moderate: 40-55 mm; large: > 55 mm).ResultsFMD is inversely correlated with the diameter of AAAs in all patients (n=162, Spearman's r=-.28, p<.001). FMD is inversely correlated with AAA diameter progression in the future 12 months (Spearman's r=-.35, p=.001), particularly in the moderate size group. Furthermore, FMD deteriorates during the course of AAA surveillance (from a median of 2.0% at baseline to 1.2% at follow-up; p=.004), while surgical repair of AAAs (n=50 [open repair n=22, endovascular repair n=28)] leads to an improvement in FMD (from 1.1% pre-operatively to 3.8% post-operatively; p<.001), irrespective of the type of surgery.ConclusionFMD is inversely correlated with future AAA progression in humans. FMD deteriorates during the natural history of AAA, and is improved by surgery. The utility of FMD as a potential biomarker in the context of AAA warrants further investigation.
| S-EPMC5496669 | biostudies-literature
Project description:OBJECTIVES: Abdominal aortic aneurysm (AAA) rupture has a high mortality rate. Although the diagnosis of a ruptured AAA is usually straightforward, detection of impending rupture signs can be more challenging. Early diagnosis of impending AAA rupture can be lifesaving. Furthermore, differentiating between impending and complete rupture has important repercussions on patient management and prognosis. The purpose of this article is to classify and illustrate the entire spectrum of AAA rupture signs and to review current treatment options for ruptured AAAs. METHODS: Using medical illustrations supplemented with computed tomography (CT), this essay showcases the various signs of impending rupture and ruptured AAAs. Endovascular aneurysm repair (EVAR) and open surgical repair are also discussed as treatment options for ruptured AAAs. RESULTS: CT imaging findings of ruptured AAAs can be categorised according to location: intramural, luminal, and extraluminal. Intramural signs generally indicate impending AAA rupture, whereas luminal and extraluminal signs imply complete rupture. EVAR has emerged as an alternative and possibly less morbid method to treat ruptured AAAs. CONCLUSIONS: AAA rupture occurs at the end of a continuum of growth and wall weakening. This review describes the CT imaging findings that may help identify impending rupture prior to complete rupture. TEACHING POINTS: • AAA rupture occurs at the end of a continuum of growth and wall weakening. • Intramural imaging findings indicate impending AAA rupture. • Luminal and extraluminal imaging findings imply complete AAA rupture. • Some imaging findings are not specific to AAA ruptures and can be seen in other pathologies. • EVAR has emerged as an alternative and possibly less morbid method of treating ruptured AAAs.
| S-EPMC4035490 | biostudies-other
Project description:Background The protective effects of polyamines on cardiovascular disease have been demonstrated in many studies. However, the roles of spermidine, a natural polyamine, in abdominal aortic aneurysm (AAA) disease have not been studied. In this study, we investigated the influence and potential mechanisms of spermidine treatment on experimental AAA disease. Methods and Results Experimental AAAs were induced in 8- to 10-week-old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase. Spermidine was administered via drinking water at a concentration of 3 mmol/L. Spermidine treatment prevented experimental AAA formation with preservation of medial elastin and smooth muscle cells. In immunostaining, macrophages, T cells, neutrophils, and neovessels were significantly reduced in aorta of spermidine-treated, as compared with vehicle-treated elastase-infused mice. Additionally, flow cytometric analysis showed that spermidine treatment reduced aortic leukocyte infiltration and circulating inflammatory cells. Furthermore, we demonstrated that spermidine treatment promoted autophagy-related proteins in experimental AAAs using Western blot analysis, immunostaining, and transmission electron microscopic examination. Autophagic function was evaluated for human abdominal aneurysmal and nonaneurysmal adjacent aortae from AAA patients using Western blot analysis and immunohistochemistry. Dysregulated autophagic function, as evidenced by increased SQSTM1/p62 protein and phosphorylated mTOR, was found in aneurysmal, as compared with nonaneurysmal, aortic segments. Conclusions Our results suggest that spermidine supplementation limits experimental AAA formation associated with preserved aortic structural integrity, attenuated aortic inflammatory infiltration, reduced circulating inflammatory monocytes, and increased autophagy-related proteins. These findings suggest that spermidine may be a promising treatment for AAA disease.
| S-EPMC7428527 | biostudies-literature